EP1793868B1 - Agents de contraste liposomaux pour technologie d'imagerie cest - Google Patents

Agents de contraste liposomaux pour technologie d'imagerie cest Download PDF

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EP1793868B1
EP1793868B1 EP05801399A EP05801399A EP1793868B1 EP 1793868 B1 EP1793868 B1 EP 1793868B1 EP 05801399 A EP05801399 A EP 05801399A EP 05801399 A EP05801399 A EP 05801399A EP 1793868 B1 EP1793868 B1 EP 1793868B1
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iii
liposome
liposomes
protons
cest
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EP1793868A2 (fr
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Marc Port
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Guerbet SA
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Guerbet SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • A61K49/1812—Suspensions, emulsions, colloids, dispersions liposomes, polymersomes, e.g. immunoliposomes

Definitions

  • the invention refers to contrast agents encapsulating systems, liposomes carrying lanthanides chelates, for CEST imaging.
  • MRI Magnetic Resonance Imaging
  • Many contrast agents i.e. chemicals able to promote marked changes in the relaxation rates of the tissue protons, have been described, particularly T1 agents represented by paramagnetic complexes, mostly containing GD(III) or Mn(II) ions. These complexes affect the relaxation rates of the bulk water through the exchange of the water molecules in their coordination spheres ( Caravan P, et al. Chem. Rev 1999, 99:2293-2352 ; the Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging. Chichester, UK: John Wiley & Sons; 2001. p 45-120 ).
  • the proton relaxivity is a measure for the ability of the paramagnetic substance to accelerate the nuclear relaxation of water protons in the media where this paramagnetic substance has been dissolved.
  • a good contrast agent for CEST imaging has to possess mobile protons, whose exchange rate with water is as high as possible before their broadening makes the rf irradiation ineffectual. Larger chemical shift differences enable the exploitation of faster exchange, resulting in an enhanced CEST effect.
  • a ⁇ more than 2 ppm is preferable in order not to irradiate the bulk water.
  • a high ⁇ allows the use of a large irradiating zone, and minimises the transfer saturation effects between endogenous water and bulk water.
  • WO 00/66180 describes compounds that are diamagnetic organic molecules such as sugars, amino acids, nitrogen-containing heterocycles, purines, guanidine, nucleosides, imidazole and derivatives thereof, barbituric acid and analogous thereof, wherein heterocyclic compounds having exchangeable OH or NH groups such as 5,6- dihydrouracil, 5-hydroxytryptophan are particularly preferred when the pH is determined according to claimed method.
  • the diamagnetic systems are advantageously endowed with short relaxation rates.
  • the chemical shifts of exchangeable protons thereof are only slightly shifted (1-5 ppm) from bulk water signal and, therefore, slower exchange rate can be exploited before coalescence takes place.
  • Sherry et al. showed that a particularly useful source of highly shifted exchangeable protons can be provided by the slowly exchanging water protons bound to a paramagnetic Eu(III)-chelate.
  • the irradiation of such protons which resonate at 50 ppm downfield from the bulk water signal, determined a significant CEST effect in the images obtained at 4.7 T.
  • Sherry et al. in J Am Chem. Soc 2001, 123:1517-1518 determined a significant CEST effect in the images obtained at 4.7 T.
  • no contrast is detectable if the uptake between the target and the surrounding tissue is similar.
  • these contrast agents in general, allow the production of images of the targeted tissue or organ but they all are unable to measure the metabolic conditions of the examined tissue and to refer about the physico-chemical parameters determining thereof.
  • the mobile protons studied are the water protons linked to the lanthanide in the inner sphere of the chelate and/or the protons of amides linked in the first coordination sphere of the lanthanide.
  • the value ⁇ is better with these agents.
  • the DOTA tetraamides are designed in order to have a low water exchange (water linked in the inner sphere) and to use the amides protons (linked in the inner sphere). It is reminded that the inner sphere corresponds to the water molecules that are in contact with the metal ion in the complex and that are in fast exchange with the bulk water molecules
  • EP 1 466 629 which is a document according to Article 54(3) EPC describes substrates adducts [SR-SH] for Cest imaging, that may be endalized in a liposome in which SR is Ln [DOTP] 4- wherein Ln is a lanthanide selected from Cerium (III), Praseodymium (III), Neodymium (III), Dysprosium (III), Erbium (III), Terbium (III), Holmium (III), Thulium (III), Ytterbium (III) and Europium (III) and SH is a diamagnetic substrate selected from linear and cyclic polyamines, polyaminoacids, proteins, polysaccharides, polyamidoamines, peramidated polyaminoacids, dendrimers containing amide groups, polycyclodextrins, polysaccharides and alginates.
  • Ln is a lanthanide selected from Cerium (III), Praseodymium (III), Ne
  • the applicant has now identified a totally different approach for obtaining a very satisfying sensibility of the CEST imaging. Indeed the applicant has studied products exhibiting a pool with a very high number of mobile protons. This pool is obtained with an encapsulating system (ES), being liposomes , that encapsulate the mobile protons.
  • ES encapsulating system
  • the energy required is much lower as described hereafter. This would be due to the low dispersion of the shift and to the water exchange rate of the encapsulating systems: the protons behave similarly in the encapsulating systems.
  • the invention relates to the use of a contrast agent in a method for CEST imaging wherein said contrast agent comprises a proton pool Encapsulating System (ES) that contains a pool of water mobile shifted protons as claimed in claim 1 and in claim 2.
  • ES proton pool Encapsulating System
  • Said contrast agent comprises a proton pool encapsulating system that contains 1) a pool of water mobile protons to be shifted and 2) a shift agent.
  • Said encapsulating system ES is any encapsulating system with water entrapped, being a liposome.
  • the agent can have only a part within the encapsulating system, and an other part not entrapped part (at least a part located inside the lipid layer or even outside) since this latter part implies only a low shift of the bulk water. It is for instance possible to covalently link the cest agent (the chelate) to a phospholipid inserted in the encapsulating system. For this, the chelate is coupled, eventually with a linker, to a lipophilic chain of a phospholipid of the ES membrane. The protons of the protons pool are shifted due to the shift agent.
  • the shift agent is a paramagnetic complex of a lanthanide.
  • Said lanthanide is chosen among Erbium (II), Europium (III), Dysprosium (III), Gadolinium (III), Praseodymium (III), Neodymium (III), Terbium (III), Holmium (III), Thulium (III), Ytterbium (III)
  • the ES (the liposomes) forming lipids comprise phospholipids or hydrogenated phospholipids or derivatives thereof among phosphatidylcholines (lecithins) (PC), phosphatidylethanolamines (PE), lysolecithins, lysophosphatidylethanolamines, phosphatidylserines (PS), phosphatidylglycerols (PG), phosphatidylinositol (PI), sphingomyelins, cardiolipin, phosphatidic acids (PA), fatty acids, gangliosides, glucolipids, glycolipids, mono-, di or triglycerides, ceramides or cerebrosides.
  • PC phosphatidylcholines
  • PE phosphatidylethanolamines
  • PS phosphatidylglycerols
  • PI phosphatidylinositol
  • PA phosphatidic acids
  • fatty acids
  • a mixture of saturated and unsaturated phospholipids and of cholesterol is used, notably in the proportion 40/10/50 to 60/5/35 for instance 55/5/40.
  • the ES is a liposome formed with phospholipids having an intermediate HLB value in the order of 10.
  • the ES are of diameter of range 20-5000 nm.
  • the ES (the liposomes) structure is adapted for blood pool imaging.
  • the ES (the liposomes) structure is adapted for specific targeting.
  • the specific targeting refers to the targeting of a biological target such as a tissue or a pathologic area, recognized specifically by the contrast agent.
  • the encapsulating system comprises a least a targeting biovector and are thus very useful for molecular imaging.
  • the invention also relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a physiological acceptable carrier and a contrast agent as described above.
  • the invention relates to:
  • Liposomes encapsulating lanthanides chelates are known but the prior art neither describes nor suggests to use of liposome technology for CEST imaging. Further the liposomes have to be appropriate for the CEST imaging.
  • An encapsulating system ES refers to liposomes for convenience the term ES/liposomes is also used.
  • the liposomes are spherical vesicles having a lipid layer surrounding a central space.
  • the present invention is particularly concerned with unilamellar and multilamellar liposomes which respectively have a single lipid bilayer or multiple lipid bilayers surrounding an aqueous core. Liposomes comprising multiple lipid bilayers are also called spherulites.
  • Liposomes spontaneously form upon dispersion of lipids, particularly phospholipids, in aqueous media and the liposomal structure of the agents of the invention can be produced by conventional techniques. Such conventional techniques are referred to in WO92/21017 (Unger ) and by Papahadjopolous in Ann Rep. Med. Chem. 14: 250-260 (1979 ) and include reverse evaporation, freeze-thaw, detergent dialysis, homogenization, sonication, microemulsification and spontaneous formation upon hydration of a dry lipid film. Multi-lamellar liposomes can be used according to the invention or may be converted to liposomes with lower lamellarity, or to unilamellar liposomes, by known methods. Unilamellar liposomes can also be prepared directly.
  • Liposome preparations are typically heterogeneous in size and the liposomes used according to the invention may be sized to the desired diameter by known techniques, eg. extrusion, freeze-thaw, mechanical fragmentation, homogenization and sonication.
  • the liposomes used according to the invention are advantageously 20-5000 nm diameter, unilamellar or multi-lamellar.
  • the ES/liposomes may be lyophilized to increase shelf life and lyophilized ES/liposomes may be reconstituted by vigorous shaking with aqueous buffer prior to use.
  • Formulations may include agents which serve to stabilize the ES/liposomal material for the lyophilization procedure.
  • Liposomes smaller than 200 nm may be sterilized after formulation by filtration.
  • the lipids used as the liposomal membrane forming molecules and more generally as the ES membrane forming molecules are typically phospholipids or hydrogenated phospholipids such as natural or synthetic phosphatidylcholines (lecithins) (PC), phosphatidylethanolamines (PE), lysolecithins, lysophosphatidylethanolamines, phosphatidylserines (PS), phosphatidylglycerols (PG), phosphatidylinositol (PI), sphingomyelins, cardiolipin, phosphatidic acids (PA), fatty acids, gangliosides, glucolipids, glycolipids, mono-, di or triglycerides, ceramides or cerebrosides, eg. liposome membrane forming compounds such as are described in WO-92/21017 .
  • the membrane forming lipids may also comprise polymerizable lipids, e.g. methacrylate lipids, thiol and disulphide lipids, dienoate lipids, styryl lipids and diacetylanic lipids as described by Johnston in Liposome Technology Vol. I, Gregoriades Ed., pages 123-129 (1983 ) and Singh in Phospholipid Handbook, Cevc Ed., Dekker, pages 233-291 (1993 ) and references therein.
  • polymerizable lipids e.g. methacrylate lipids, thiol and disulphide lipids, dienoate lipids, styryl lipids and diacetylanic lipids as described by Johnston in Liposome Technology Vol. I, Gregoriades Ed., pages 123-129 (1983 ) and Singh in Phospholipid Handbook, Cevc Ed., Dekker, pages 233-291 (1993 ) and references therein
  • the ES and liposomal membrane can also have steroids and other compounds incorporated into it, eg. to affect the biodistribution of the liposome.
  • steroids include for example cholesterol, cholesterol derivatives, cholestane, cholic acid, and bile acids, but particularly cholesterol.
  • biodistribution modifiers can be incorporated by the use of a phospholipid derivative having a pendant biodistribution modifying function, by the use of a biodistribution modifying agent having a hydrophobic "anchor" moiety which associates with the ES or liposomal membrane or by coupling a biodistribution modifier to an anchor molecule (such as discussed above in relation to chelate tethering) present in the liposomal membrane.
  • biodistribution modifiers also called furtive agents
  • Polyalkyleneoxy polymers such as polyethylene glycol (PEG) and gangliosides, such as Gm.sub.1, are effective in this regard.
  • Double emulsions which do not form part of the present invention refer to emulsions water/oil/water being dispersions of oily globules in which water drops have been prior dispersed.
  • two surfactants used for the double emulsion are such that their respective HLB allows the formation of the globules, one surfactant with high HLB, the other surfactant with low HLB.
  • the ratio is such that the efflux of water can be controlled between the inside and the outside of the globules.
  • Double emulsions are for instance described in "how does release occur?" Pays K, Giermanska-Kahn J, Pouligny B, Bibette J, Leal-Calderon F, J Control Release.
  • liphophilic complexes such as Dy3+ or Tm3+ DTPA BC14A to be incorprated in the liposome.
  • the complexes inserted in the outer layer are transmetallated with a non shift metal agent such as La3+.
  • the transmettallation by a T1 or T2 relaxer metal can provide multimodal CEST/T1 MRI contrast agent.
  • Spacer may include a part issued from a phosphoglyceride, for example a CH 2 CH 2 from a phosphodiglyceride such as phosphatidyl ethanolamine. Spacer may include groups derivated from peptides, pseudopeptides, polyalkylene glycols, PEG and analogues. In such ES systems, the chelate may be present.
  • ES/Liposome biodistribution is also significantly dependent upon surface charge and the liposomes according to the invention may desirably include 1 to 10%, relative to the weight of liposome membrane forming material, of negatively charged phospholipids such as for example phosphatidylserine, phosphatidylglycerols, phosphatidic acids, and phosphatidylinositol.
  • negatively charged phospholipids such as for example phosphatidylserine, phosphatidylglycerols, phosphatidic acids, and phosphatidylinositol.
  • Liposomes for encapsulating lanthanides chelates complexes are described for instance in EP 314 764 , WO 9625955 and WO2004023981 .
  • the neutral phospholipids comprise the usual saturated and unsaturated phosphatidylcholines and ethanolamines, for instance, the corresponding mono- and di-oleoyl-, mono-and di-myristoyl-, mono- and di-palmitoyl-, and mono- and di-stearoyl- compounds.
  • the negatively charged phospholipids comprise the phosphatidyl glycerols preferably dimyristoylphosphatidyl glycerol (DMPG), dipalmitoylphosphatidyl glycerol (DPPG), distearoylphosphatidyl glycerol (DSPG) and optionally the corresponding phospholipids where the glycerol is replaced by inositol.
  • DMPG dimyristoylphosphatidyl glycerol
  • DPPG dipalmitoylphosphatidyl glycerol
  • DSPG distearoylphosphatidyl glycerol
  • the lipids of the liposomes may contain additives commonly present in liposome formulations, like the sterols and some glycolipids; the sterols may include cholesterol, ergosterol, coprostanol, cholesterol esters such as the hemisuccinate (CHS), tocopherol esters.
  • CHS
  • the glycolipids may include cerebrosides, galacto-cerebrosides, glucocerebrosides, sphingo-myelins, sulfatides and sphingo-lipids derivatized with mono-, di- and trihexosides.
  • ES/liposomes may be such as those described in WO2004023981 which describes liposomes not sensitive to the biological environment and liposomes that are sensitive to the biological environment.
  • An envirosensitive liposome can comprise, for example, a thermosensitive liposome, a pH-sensitive liposome, a chemosensitive liposome and a radiation-sensitive liposome.
  • thermosensitive liposomes can be formed from a combination of lipids that comprises :
  • Liposomes may be as described in US 6 045 821 which presents liposomal agents in which metal chelate moieties are tethered to the liposomal membrane, in particular using macrocyclic chelant moieties having a lipophilic anchor group attached at only one ring atom, the macrocyclic chelant and anchor groups preferably being coupled to each other, advantageously via a biodegradable bond, after liposome formation.
  • liposomal agents will generally include, besides the anchor/chelate molecules, liposome membrane forming compounds, i.e. lipids and in particular phospholipids, as well as the materials which make up the liposome core and its external environment, generally in each case an aqueous medium.
  • liposome membrane forming compounds i.e. lipids and in particular phospholipids
  • the chelated metals are tethered internally (and eventually also externally) to the liposomes in several ways, for example:
  • the ES liposomes may comprise phospholipids with short acyl chain lengths such as DMPC (dimyristoyl phosphatidyl choline), DPPC (Dipalmitoylphosphatidylcholine), DPPG (Dipalmitoylphosphatidylglycerol) and DMPG (dimyristoyl phosphatidyl glycerol).
  • the ES/liposomes composition may advantageously be adapted in order to adjust the water exchange property of the liposomes.
  • Such adaptation is described notably in International Journal of Pharmaceuticals, 233, 2002,131-140 , Glogard et al.
  • a high level of cholesterol may rigidify the liposomes membrane and decrease the water exchange across the membrane.
  • a reduced surface area-to-volume ratio and the presence of multilamellar bilayers will slow down the water exchange between the liposome interior and exterior.
  • active targeting to specific organs or tissues can be achieved by incorporation of lipids with attached thereto biovectors such as monoclonal antibodies or antibody fragments that are specific for tumour associated antigens, lectins or peptides.
  • biovectors such as monoclonal antibodies or antibody fragments that are specific for tumour associated antigens, lectins or peptides.
  • Targeting liposomes ES are notably described in US 6 350 466 wherein the liposomes comprise a targeting agent attached to hydrophilic head groups of a portion of lipids in the lipid sheet.
  • Biovectors may be appropriately coupled with lipophilic groups allowing the insertion into the ES membrane such that the biovector is at least displayed on the external face of the ES.
  • Targeting delivery of imaging agents by liposomes is also well described in Handbook of Targeting delivery of imaging agents, Ed Wladimir P.torchilin, Massachusetts, 1995, pages 149-155 and 403, namely relating to tumours and inflammation. For instance large unilamellar liposomes LUV may be used.
  • biovectors Many targeting entities (called biovectors) can be used, notably those mentioned in WO 2004/112839 notably pages 65 to 82, in particular among the followings :
  • the specific targeting CEST agents can also include at least two different encapsulating systems having different targeting moities and metals (cocktail of encapsulating systems containing different targeting biovectors and cest agents).
  • a diagnostic agent can comprise a mixture of i) ES/liposomes incorporating Tm3+ and a biovector specific for metalloprotease MMP1 and ii) liposomes with Dy3+ and a biovector for metalloprotease MMP9.
  • the targeting moieties may target ligands associated to different mechanisms, for instance associated to angiogenesis and ligands associated to targets.
  • CEST systems of the invention can be also used for stem cells taging.
  • the lipasomes are formulated in pharmaceutically physiologically tolerable liquid carrier medium, eg. an aqueous solution which may include one or more additives, such as pH modifying agents, chelating agents, antioxidants, tonicity modifying agents, cryoprotectants, further contrast agents, etc.
  • pharmaceutically physiologically tolerable liquid carrier medium eg. an aqueous solution which may include one or more additives, such as pH modifying agents, chelating agents, antioxidants, tonicity modifying agents, cryoprotectants, further contrast agents, etc.
  • suitable ingredients to adjust the pH include physiologically tolerable acids, bases and buffers, such as acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, phosphoric acid, sulfuric acid, or tartaric acid, ammonia, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine, ammonium phosphate, boric acid, citric acid, lactic acid, potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium biphosphate, sodium citrate, sodium lactate, sodium phosphate, Tris, and N-methyl glucamine.
  • physiologically tolerable acids, bases and buffers such as acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, phosphoric acid, sulfuric acid, or tartaric acid, ammonia, ammonium carbonate, diethanolamine, diisopropanolamine
  • Suitable anti-oxidants include ascorbic acid, ascorbyl palmitate, cysteine, monothioglycerol, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphoric acid, propyl gallate, sodium bisulfate, sodium formaldehyde sulfoxylate, sodium metabisulfate, sodium thiosulfate, sulfur dioxide, or tocopherol.
  • suitable tonicity agents include sodium chloride, glucose, sucrose, mannitol, sorbitol and dextrose. These agents preferably are used to make the formulation isotonic or near isotonic with blood.
  • Suitable anti-microbial agents include, benzalkonium chloride, benzyl alcohol, chlorobutanol, metacresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, and timerosal.
  • the responsive paramagnetic agent for use in the encapsulating systems of the invention includes at least one chelated complex of a paramagnetic metal ion adapted for CEST imaging.
  • the paramagnetic metal ion is a lanthanide (III) metal ion which has an electronic relaxation time suitably short to significantly affect the chemical shift value of the mobile protons to be irradiated for CEST.
  • paramagnetic metal ions selected in the group consisting of cerium (III), praseodymium(III), neodymium (III), gadolinium (III), dysprosium (III), erbium (III), terbium (III), holmium (III), thulium (III), ytterbium (III), and europium (III).
  • cerium (III) praseodymium(III), neodymium (III), gadolinium (III), dysprosium (III), erbium (III), terbium (III), holmium (III), thulium (III), ytterbium (III), and europium (III).
  • Dy3+, Tb3+, Tm3+,Yb3+, Eu3+ are particularly preferred.
  • Suitable chelating agents include DOTA, DTPA, DTPA-BMA, BOPTA, DO3A, PCTA, derivatives thereof (described for instance in Mini Reviews in Medicinal Chemistry, 2003, vol 3, n°8 ), and salts and complexes thereof especially calcium, sodium or meglumine salts, eg. edetate disodium, edetic acid, calcium EDTA.
  • Preferred paramagnetic complexes for use in the method of the invention are the chelates of the macrocyclic of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and their tetra amide derivatives as for example described in Accounts of Chemical Research, 2003, 36, 10, 783-790 .
  • DOTA 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid
  • DBP 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraphosphonic acid
  • DO3A 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid
  • HPDO3A HPDO3A or DO3AB
  • Preffered lanhtanides are Yb(III), Tm(III), Er(III), Ho(III), Dy(III) and Eu(III).
  • Chelate(s) may be also chosen among Yb(III) DOTAM-Gly an Eu(III) DOTAM-Gly or Tm-DOTAM-Gly and Eu-DOTAM-Gly described in WO9625955 , DOTMA-Tm or DOTMA-Dy or DOTA-Dy or DOTA Tm or HPDO3A-Dy or HPDO3A-Tm.
  • the invention also describes a screening method, and the compounds obtained thereof, for the identification of efficient compounds comprising a chelate shift agent and a metal, said method comprising coupling the chelate metal complex in a ES, carrying CEST imaging, and selecting the compounds.
  • a composition useful in the method of the invention may comprise ES/liposomes comprising a first chelate of a metal paramagnetic ion and liposomes comprising another chelate of a metal paramagnetic ion.
  • Parameters of interest include non exclusively temperature, pH, metabolite concentration, 02 or CO2 partial pressure, enzymatic activity, in a human or animal body organ or tissue.
  • the pharmaceutical preparations according to the invention can be suitably injected intravasally (for instance intravenously, intraarterially, intraventricularly, and so on) or used by way of intrathecal, intraperitoneal, intralymphatic, intracavital, oral or enteral administration.
  • the injectable pharmaceutical formulations are typically prepared by dissolving the active ingredient(s) and the pharmaceutically acceptable excipients in water of suitable purity from the pharmacological point of view.
  • the resulting formulation is suitably sterilised and can be use as such or it can alternatively be lyophilised and reconstructed before the use.
  • formulations can be administered in concentrations depending on the diagnostic requirements, at a dose ranging from 0.01 to 0.5 mmol/kg body weight.
  • Imaging parameters can be as follows:
  • a chelate DOTA or DOTAMGly or DOTAM as shift agent is entrapped within a liposome encapsulating system obtained from a mixture of saturated and unsaturated phospholipids and cholesterol sodium salts. For instance 50:10:40 or 55:15:30 w/w/w of dipalmitoylphosphatidyl glycerol DPPG/ oleoyl palmitoyl phosphatidylcholine / cholesterol.
  • Liposome prepared using solutions of DOTA of 0.1 to 1 M allow to obtain a concentration of DOTA inside the liposomes of 0.05 to 0.5 M.
  • the liposome prepared have a concentration of shift agent in the range 0.5 to 5 mM, the concentration of liposomes being for instance in the range 1 to 5 nM, preferably 2-4 nM.
  • the mean diameter of liposomes is around 0.2 to 0.3 ⁇ m, notably depending of the cholesterol ratio.
  • Imaging parameters Bruker 7 T, 312 DEG K, 3s irradiation time. The field required to obtain good results is much lower than for liposomes containing the shift agent than for a shift agent not entrapped in liposomes. Contrast CEST images can be obtained even at a concentration of liposome in the order of 0.05 nM or even less according to the concentration of shift agent used in the liposomes.
  • Example 2 DOTA or DTPA lipophilic derivatives are prepared according to prior art : US 6 045 821 (macrocyclic chelates notably DO3A-succinyl-PE, DO3A-glutaryl-PE, DO3A-DOBA, DO3A-DOmBA, DO3A-DOoBA DO3A-DOIA, DO3A-HOBA, DO3A-OOBA and AE-DO3A-dodecenyl-PE ; see examples 3 to 24), US 5 154 914 (DTPA carrying lipophilic chains C1-C30), US 5 312 617 (DTPA with to lipophilic groups CH 2 CONR).
  • US 6 045 821 macrocyclic chelates notably DO3A-succinyl-PE, DO3A-glutaryl-PE, DO3A-DOBA, DO3A-DOmBA, DO3A-DOoBA DO3A-DOIA, DO3A-HOBA, DO3A-OOBA and AE-DO
  • the chelate shift agent is coupled to the phospholipidic membrane.
  • the chelate is located either at the external face of the liposome membrane ("external chelate”) or at the internal face (“internal chelate”).
  • Liposomes were prepared by the thin film method as follows: DSPC, the lipophile Tm complexe, FA-PEG-DSPE and cholesterol were co-dissolved in chloroform/methanol mixture 1:1 (v/v) and were evaporated to dryness under reduced pressure.
  • the total amount of lipids was typically 120 ⁇ mol composed of:
  • the lipid film was then rehydrated with 3ml of buffer at pH 6.5 constituted by 20 mM HEPES and 135 mM NaCl.
  • Tc transition temperature
  • the phospholipids concentration was determined by phosphorus analysis according Rouser (1970).
  • the efficiency of Tm chelate incorporation was analysed by inductively coupled plasma atomic emission spectroscopy (ICP-AES)
  • the mean diameter of the liposomes was measured at 90° angle (25°C) by photon correlation spectroscopy (PCS) with a Malvern 4700 system : around 120nm.
  • the preparation method may include a step of transmetallation of the "external chelate".
  • a transmetallation solution is added to the composition comprising the liposomes displaying both "internal chelate” and “external chelate”.
  • the transmetallation solution comprises La 3+ and allows to complex the metal of the "external chelate”.
  • the "external chelate” is in terms of CEST shift effect desactivated.
  • Dysprosium and thullium complex of the ester of acid octadecanoic3-( ⁇ 2-[4-(3,9-bis-carboxymethyl-3,6,9,15-tetraaza-bicyclo[9.3.1]pentadeca-1(14),11(15), 12-trien-6-yl)-4-carboxy-butyrylamino]-ethoxy ⁇ -hydroxy-phosphoryloxy)- 2-octad6canoyloxy-propylic 200 mg of compound Ln Tm or Dy are dissolved in 10 ml of Dimethylformamide. To this solution are added 204 mg of N,N'-dicyclohexylcarbodiimide and 40mg of N-hydroxysuccunimide.
  • the mixture is steered 1 h at room temperature and a solution of 250 mg of 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine (DSPE, AVANTI ® Polar Lipids, Inc.) in 5 ml of pyridine is added.
  • the reactive medium is steered 20h at room temperature and precipitated in 50 ml ethanol
  • Example 4 liposome preparation of DTPA derivatives, with PEG inserted furtive agents
  • the chelate complexes are encapsulated within the liposomes, in the aquous internal phase :
  • Liposomes were prepared by the thin film method as follows: phospholipids (DPPC and DPPG), FA-PEG-DSPE and cholesterol were co-dissolved in chloroform/methanol mixture 5:1 (v/v) and were evaporated to dryness under reduced pressure. The total amount of lipids was typically composed of:
  • the lipid film was then rehydrated with an aqueous solution of 0,25M Dy-DTPA-BMA.
  • the multilamellar vesicles were treated by freeze-thaw five times.
  • the resulting large oligolamellar vesicles liposomes were extruded under pressure through double polycarbonate membrane filters (100 and 50 nm pore diameter).
  • Unentrapped chelate of Dy was removed by dialysis with Spectra/Por membrane (molecular weight cut off: 10000 daltons) against buffer pH 7,4 constituted by 20 mM HEPES and 135 mM NaCl.
  • the phospholipids concentration was determined by phosphorus analysis according Rouser (1970).
  • the efficiency of Dychelate incorporation was analysed by inductively coupled plasma atomic emission spectroscopy (ICP-AES)
  • the mean diameter of the liposomes was measured at 90° angle (25°C) by photon correlation spectroscopy (PCS) with a Malvern 4700 system : around 110nm.
  • Example 5 lipophilic non peptidic (folic acid derivatives) biovector coupled to encapsulating systems
  • step 1
  • Step 2 Acylation of peptides
  • Peptides are prepared on solide phase by using 2.5 equivalents of each aminoacid protected Fmoc at each coupling cycle.
  • the activation of the carboxylic acids is made with HATU, N-methylmorpholine in DMF.
  • the Fmoc groups are coupled by a piperidine treatment (20% in DMF).
  • the N-terminal amine of the peptide is acylated by the compound prepared at step 1 (2.5 herebys) dissolved in CH 2 Cl 2 with presence of HoBt and N-methylmorpholine.
  • the peptide is afterwards liberated from the resin and the protecting groups of the lateral functions are cut by action of a mixture of acid trifluoroacetique/thioanisole (95/5) during 30 minutes art 0°c and followed by 2h at room temperature.
  • the resin is eliminated and the solvant is evaporated at low pressure.
  • the lipopeptide is precipitated in ether ethylic.
  • the products are purified by HPLC preparative on column Vydac ODS® by eluting with a mixture water/acetonitrile/TFA. Structure Moclecular weight ES+ m/z 901.08 902.5 983.40 986 882.12 884
  • Such lipophilic PEG derivatives are well known, commercialy available for instance from AVANTI®polar lipids on Avantilipids.com, notably PEG 350, 750, 2000, 3000, 5000, in particular:
  • Multilamelar liposomes (or MLV, multilamelar vesicule) were prepared by the thin film method as follows: phospholipids (DPPC and DPPG), FA-PEG-DSPE and cholesterol were co-dissolved in chloroform/methanol mixture 5:1 (v/v) and were evaporated to dryness under reduced pressure.
  • the total amount of lipids was typically composed of:
  • the phospholipids concentration was determined by phosphorus analysis according Rouser (1970).
  • the efficiency of Dy ot Tm chelate incorporation was analysed by inductively coupled plasma atomic emission spectroscopy (ICP-AES)
  • the mean diameter of the liposomes was measured at 90° angle (25°C) by photon correlation spectroscopy (PCS) with a Malvern 4700 system: around 600 nm.
  • the W/O/W double microemulsion was prepared in two steps.
  • a warm W/O microemulsion was first prepared by adding an aqueous solution (3 to 10%) at 70°C containing the Dy-DOTA (0.05-0.2 M) to a mixture of:
  • the W/O/W double emulsion was obtained by adding to the warm W/O microemulsion (10 to 15%) a mixture warmed at 70°C of:

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Claims (18)

  1. Utilisation d'un produit de contraste CEST dans un procédé d'imagerie CEST, pour laquelle le produit de contraste comprend un système d'encapsulation d'un pool de protons, lequel est un liposome, qui contient 1) un pool de protons mobiles de l'eau à déplacer et 2) un complexe paramagnétique d'un lanthanide, à l'exception d'un adduit [(SR)(SH)] compartimentalisé dans un liposome dans lequel SR est Ln[DOTP]4- où Ln est un lanthanide choisi parmi le cérium(III), le praséodyme(III), le néodyme(III), le dysprosium(III), l'erbium(III), le terbium(III), le holmium(III), le thulium(III), l'ytterbium(III) et l'europium(III), et SH est un substrat diamagnétique choisi parmi les polyamines linéaires et cycliques, les poly(acides aminés), les protéines, les polysaccharides, les polyamidoamines, les poly(acides aminés) peramidés, les dendrimères contenant des groupes amide, les polycyclodextrines, les polysaccharides et les alginates.
  2. Utilisation d'un produit de contraste CEST dans un procédé d'imagerie CEST, pour laquelle le produit de contraste comprend un système d'encapsulation d'un pool de protons, lequel est un liposome, qui contient 1) un pool de protons mobiles de l'eau à déplacer, et 2) un complexe paramagnétique d'un lanthanide, la structure du système d'encapsulation étant apte à cibler d'une manière active des organes ou des tissus spécifiques par incorporation de lipides, auxquels sont fixés des biovecteurs choisis parmi les anticorps monoclonaux ou les fragments d'anticorps qui sont spécifiques d'antigènes associés à des tumeurs, des lectines et des peptides.
  3. Utilisation de la revendication 1 ou 2, pour laquelle le groupe chélatant du complexe paramagnétique est choisi parmi DOTA, DTPA, DTPA-BMA, BOPTA, D03A, PCTA, les dérivés du DOTA, du DTPA, du DTPA-BMA, du BOPTA, du PCTA et du D03A, DOTAMgly, les dérivés trisamidés du D03A et du PCTA, et les dérivés tétraamidés du DOTA.
  4. Utilisation des revendications 1 à 3, pour laquelle ledit lanthanide est choisi par l'erbium(II), l'europium(III), le dysprosium(III) le gadolinium(III), le praséodyme(III), le néodyme(III), le terbium(III), l'holmium(III), le thulium(III), l'ytterbium(III).
  5. Utilisation de la revendication 4, pour laquelle ledit lanthanide est choisi parmi l'europium(III), le dysprosium(III) et l'ytterbium(III).
  6. Utilisation de la revendication 4, pour laquelle ledit complexe paramagnétique est un chélate choisi parmi Yb(III)DOTAM-Gly, Tm(III)DOTAM-Gly et Eu-DOTAM-Gly.
  7. Utilisation des revendications 1 à 6, pour laquelle les lipides formant le système d'encapsulation comprennent les phospholipides ou les phospholipides hydrogénés ou les dérivés de ceux-ci parmi les phosphatidylcholines, les phosphatidyléthanolamines, les lysolécithines, les lysophosphatidyléthanolamines, les phosphatidylsérines, les phosphatidylglycérols, le phosphatidylinositol, les sphingomyélines, la cardiolipine, les acides phosphatidiques, les acides gras, les gangliosides, les glucolipides, les glycolipides, les mono-, di- ou triglycérides, les céramides ou les cérébrosides.
  8. Utilisation des revendications 1 à 7, pour laquelle des stéroïdes, notamment le cholestérol, les dérivés du cholestérol, le cholestane, l'acide cholique et les acides biliaires, sont incorporés dans la membrane liposomique.
  9. Utilisation des revendications 1 à 7, pour laquelle le liposome comprend 1 à 10 %, par rapport au poids du matériau formant la membrane liposomique, de phospholipides négativement chargés.
  10. Utilisation des revendications 1 à 10, pour laquelle le liposome comprend 1 à 10 % de dérivés de PEG-PE, par rapport au poids du matériau formant la membrane liposomique.
  11. Utilisation des revendications 1 à 10, pour laquelle le liposome a un diamètre compris dans la plage de 20 à 5000 nm.
  12. Utilisation des revendications 1 à 8, pour laquelle le chélate est attaché à la membrane liposomique.
  13. Utilisation de la revendication 12, pour laquelle le chélate est couplé à des molécules d'ancrage dans les liposomes.
  14. Utilisation des revendications 1 à 13, pour laquelle le produit de contraste comprend des liposomes comprenant un premier chélate d'un ion paramagnétique métallique et des liposomes comprenant un autre chélate d'un ion paramagnétique métallique.
  15. Utilisation des revendications 1 à 13, pour laquelle la structure du système d'encapsulation est apte à réaliser une imagerie d'un pool sanguin.
  16. Utilisation des revendications 1 à 15, pour laquelle le liposome est un liposome enviro-sensible.
  17. Procédé de détermination par IRM d'un paramètre physico-chimique dans un organe, un fluide ou un tissu corporel humain ou animal, dans lequel un produit CEST tel que défini dans les revendications 1 à 16 est utilisé, dont le pouvoir de transfert de saturation est corrélé au paramètre physico-chimique d'intérêt, et on enregistre une image IRM du CEST pour ce paramètre physico-chimique.
  18. Procédé de détermination par IRM d'un paramètre physico-chimique, comprenant l'administration, en une quantité appropriée, d'au moins un produit de contraste tel que défini dans les revendications 1 à 16, ledit produit comprenant un pool de protons mobiles en échange chimique avec les protons du milieu aqueux et apte, quand on applique un champ de rayonnement à une radiofréquence appropriée rf, à la fréquence de résonance dudit pool de protons échangeables, à réaliser un effet de transfert de saturation entre au moins une partie dudit pool mobile de protons et les protons se trouvant dans l'eau, ledit transfert de saturation étant relié au paramètre physico-chimique d'intérêt.
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